Cancer therapy is currently shifting from broadly used cytotoxic drugs to patient-specific precision therapies. Druggable driver oncogenes, identified by molecular analyses, are present in only a subset of patients. Functional profiling of primary tumor cells could circumvent these limitations, but suitable platforms are unavailable for most cancer entities. Here, we describe an in vitro drug profiling platform for rhabdomyosarcoma (RMS), using a living biobank composed of twenty RMS patient-derived xenografts (PDX) for high-throughput drug testing. Optimized in vitro conditions preserve phenotypic and molecular characteristics of primary PDX cells and are compatible with propagation of cells directly isolated from patient tumors. Besides a heterogeneous spectrum of responses of largely patient-specific vulnerabilities, profiling with a large drug library reveals a strong sensitivity towards AKT inhibitors in a subgroup of RMS. Overall, our study highlights the feasibility of in vitro drug profiling of primary RMS for patient-specific treatment selection in a co-clinical setting.
Importance: Early in the COVID-19 pandemic, chronic respiratory disease was considered a risk factor for severe COVID-19 disease. Studies have confirmed a higher risk of intensive care unit admission and mortality in people with chronic pulmonary obstructive disease and cystic fibrosis, but there is little data in people with primary ciliary dyskinesia (PCD). Objective: To study incidence of SARS-CoV-2 and its risk factors in people with PCD from May 2020 to May 2022. We also describe the severity of COVID-19 symptoms in this population and factors associated with severity. Design, setting, and participants: We used data from COVID-PCD, an international participatory cohort study following people with PCD through the COVID-19 pandemic. The study is based on self-reported weekly online questionnaires, available in five languages, adapted to children, adolescents, and adults. COVID-PCD invites people with PCD of any age to participate. Exposures: SARS-CoV-2 Main Outcomes: Incidence of reported positive test of SARS-CoV-2 and reported severity of symptoms. Results: By May 2022, 728 people with PCD participated (40% male, median age 27 years; range 0-85). The median weeks of follow-up was 60 (range 1-100). Eighty-seven (12%) reported a SARS-CoV-2 infection at baseline or during follow-up and 62 people reported an incident SARS-CoV-2 infection during 716 person-years of follow-up (incidence rate 9 per 100 person years; 95%CI 7-11). Using Poisson regression, we found that age above 14 years was associated with lower risk of infection (IRR 0.42, 95%CI 0.21-0.85) but the strongest predictors were exposure to Delta (IRR 4.52, 95%CI 1.92-10.6) and Omicron variants (IRR 13.3, 95%CI 5.2-33.8) compared to the original strain. Severity of disease was mainly mild; 12 (14%) were asymptomatic and 75 (86%) had symptoms among whom 4 were hospitalized. None needed intensive care and nobody died. Using Poisson regression, we found that comorbidity (IRR 1.93, 95%CI 1.40-2.64) and being infected during the period when the Delta variant was predominant (IRR 1.43, 95%CI 1.07-1.92) were associated with more reported symptoms. Conclusion and Relevance: People with PCD do not seem to have a higher incidence of SARS-CoV-2 infections nor higher risk of severe COVID-19 disease than people from the general population.
Diagnostic tests are important in primary ciliary dyskinesia (PCD), a rare disease, to confirm the diagnosis and characterize the disease. We compared diagnostic tests for PCD between countries worldwide, assessed whether people with PCD recall their tests, and identified factors associated with the use of tests. We used cross-sectional data from COVID-PCD—an international participatory cohort study collecting information directly from people with PCD. The baseline questionnaire inquired about tests used for PCD diagnosis. Using logistic regression, we investigated factors associated with measurement of nasal nitric oxide (nNO), biopsy for electron or video microscopy, and genetic testing. We included data from 747 participants (60% females) from 49 countries worldwide with median age 27 (interquartile range 12–44). Most (92%) reported diagnostic tests for PCD. Participants reported measurements of nNO (342; 49%), biopsy samples (561; 75%), and genetic tests (435; 58%). The reported use of individual tests, such as genetics, varied between countries from 38% in Switzerland to 68% in North America. Participant recall of test type also differed between countries with lowest recall in Switzerland. One-third (232; 36%) of participants reported all three tests (nNO, biopsy, and genetics). Recently diagnosed people reported more tests [nNO odds ratio (OR) 2.2, 95% Confidence Interval (CI) 1.5–3.2; biopsy OR 3.2, 95%CI 2.1–4.9; genetics OR 4.7, 95%CI 3.2–6.9] and those with situs abnormalities fewer tests (nNO OR 0.5, 95%CI 0.4–0.7; biopsy OR 0.5, 95%CI 0.4–0.8; genetics OR 0.7, 95%CI 0.5–0.94). Our results indicate PCD diagnostic testing differed widely around the world and many patients received incomplete diagnostic work-up based only on clinical features or single tests. People diagnosed long ago and those with situs abnormalities possibly benefit from supplementary testing to refine their diagnosis as a prerequisite for personalized medicine.
AIMS OF THE STUDY: We know little about the level of physical activity, respiratory physiotherapy practices and nutritional status of people with primary ciliary dyskinesia (PCD), although these are important aspects of patients with chronic respiratory disease. We assessed physical activity, respiratory physiotherapy practices and nutritional status among people with primary ciliary dyskinesia in Switzerland, investigated how these vary by age and identified factors associated with regular physical activity. METHODS: We sent a postal questionnaire survey to people with primary ciliary dyskinesia enrolled in the Swiss PCD registry (CH-PCD), based on the standardised FOLLOW-PCD patient questionnaire. We collected information about physical activity, physiotherapy, respiratory symptoms and nutritional status. We calculated the metabolic equivalent (MET) to better reflect the intensity of the reported physical activities. To assess nutritional status, we extracted information from CH-PCD and calculated participants’ body mass index (BMI). RESULTS: Of the 86 questionnaires we sent, 74 (86% response rate) were returned from 24 children and 50 adults. The median age at survey completion was 23 years (IQR [interquartile range] 15–51), and 51% were female. Among all 74 participants, 48 (65%) performed sports regularly. Children were vigorously active (median MET 9.1; IQR 7.9–9.6) and adults were moderately active (median MET 5.5; IQR 4.3—6.9). Fifty-nine participants (80%) reported performing some type of respiratory physiotherapy. However, only 30% of adults saw a professional physiotherapist, compared with 75% of children. Half of the participants had normal BMI; one child (4%) and two adults (4%) were underweight. People who were regularly physically active reported seeing a physiotherapist more often. CONCLUSIONS: Our study is the first to provide patient-reported data about physical activity, respiratory physiotherapy and nutrition among people with primary ciliary dyskinesia. Our results highlight that professional respiratory physiotherapy, exercise recommendations and nutritional advice are often not implemented in the care of people with primary ciliary dyskinesia in Switzerland. Multidisciplinary care in specialised centres by teams including physiotherapists and nutrition consultants could improve the quality of life of people with primary ciliary dyskinesia.
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